tbuckley/cabot-search huggingface dataset:
Chondrocyte-specific genomic editing enabled by hybrid exosomes for osteoarthritis treatment
Authors: Yujie Liang, Xiao Xu, Limei Xu, Zoya Iqbal, Kan Ouyang, Huawei Zhang, Chunyi Wen, Li Duan, Jiang Xia
Journal: Theranostics (2022)

Rationale: A cell-specific delivery vehicle is required to achieve gene editing of the disease-associated cells, so the hereditable genome editing reactions are confined within these cells without affecting healthy cells. A hybrid exosome-based nano-sized delivery vehicle derived by fusion of engineered exosomes and liposomes will be able to encapsulate and deliver CRISPR/Cas9 plasmids selectively to chondrocytes embedded in articular cartilage and attenuate the condition of cartilage damage. Methods: Chondrocyte-targeting exosomes (CAP-Exo) were constructed by genetically fusing a chondrocyte affinity peptide (CAP) at the N-terminus of the exosomal surface protein Lamp2b. Membrane fusion of the CAP-Exo with liposomes formed hybrid CAP-exosomes (hybrid CAP-Exo) which were used to encapsulate CRISPR/Cas9 plasmids. By intra-articular (IA) administration, hybrid CAP-Exo/Cas9 sgMMP-13 entered the chondrocytes of rats with cartilage damages that mimicked the condition of osteoarthritis. Results: The hybrid CAP-Exo entered the deep region of the cartilage matrix in arthritic rats on IA administration, delivered the plasmid Cas9 sgMMP-13 to chondrocytes, knocked down the matrix metalloproteinase 13 (MMP-13), efficiently ablated the expression of MMP-13 in chondrocytes, and attenuated the hydrolytic degradation of the extracellular matrix proteins in the cartilage. Conclusion: Chondrocyte-specific knockdown of MMP-13 mitigates or prevents cartilage degradation in arthritic rats, showing that hybrid CAP-Exo/Cas9 sgMMP-13 may alleviate osteoarthritis.
Cardiomyocyte-Restricted Low Density Lipoprotein Receptor-Related Protein 6 (LRP6) Deletion Leads to Lethal Dilated Cardiomyopathy Partly Through Drp1 Signaling: Erratum
Authors: Zhidan Chen, Yang Li, Ying Wang, Juying Qian, Hong Ma, Xiang Wang, Guoliang Jiang, Ming Liu, Yanpeng An, Leilei Ma, Le Kang, Jianguo Jia, Chunjie Yang, Guoping Zhang, Ying Chen, Wei Gao, Mingqiang Fu, Zheyong Huang, Huiru Tang, Yichun Zhu, Junbo Ge, Hui Gong, Yunzeng Zou
Journal: Theranostics (2022)

[This corrects the article DOI: 10.7150/thno.22177.].
Ligand Activation of PPARγ by Ligustrazine Suppresses Pericyte Functions of Hepatic Stellate Cells via SMRT-Mediated Transrepression of HIF-1α: Erratum
Authors: Feng Zhang, Shuai Lu, Jianlin He, Huanhuan Jin, Feixia Wang, Li Wu, Jiangjuan Shao, Anping Chen, Shizhong Zheng
Journal: Theranostics (2022)

[This corrects the article DOI: 10.7150/thno.22237.].
Ultrasound-directed enzyme-prodrug therapy (UDEPT) using self-immolative doxorubicin derivatives
Authors: Karolin Roemhild, Helena C. Besse, Bi Wang, Quim Peña, Qingxue Sun, Daiki Omata, Burcin Ozbakir, Clemens Bos, Hans W. Scheeren, Gert Storm, Josbert M. Metselaar, Haijun Yu, Ruth Knüchel-Clarke, Fabian Kiessling, Chrit T.W. Moonen, Roel Deckers, Yang Shi, Twan Lammers
Journal: Theranostics (2022)

Background: Enzyme-activatable prodrugs are extensively employed in oncology and beyond.Because enzyme concentrations and their (sub)cellular compartmentalization are highly heterogeneous in different tumor types and patients, we propose ultrasound-directed enzyme-prodrug therapy (UDEPT) as a means to increase enzyme access and availability for prodrug activation locally. Methods:We synthesized β-glucuronidase-sensitive self-immolative doxorubicin prodrugs with different spacer lengths between the active drug moiety and the capping group.We evaluated drug conversion, uptake and cytotoxicity in the presence and absence of the activating enzyme β-glucuronidase.To trigger the cell release of β-glucuronidase, we used high-intensity focused ultrasound to aid in the conversion of the prodrugs into their active counterparts.Results: More efficient enzymatic activation was observed for self-immolative prodrugs with more than one aromatic unit in the spacer.In the absence of β-glucuronidase, the prodrugs showed significantly reduced cellular uptake and cytotoxicity compared to the parent drug.High-intensity focused ultrasound-induced mechanical destruction of cancer cells resulted in release of intact β-glucuronidase, which activated the prodrugs, restored their cytotoxicity and induced immunogenic cell death.Conclusion: These findings shed new light on prodrug design and activation, and they contribute to novel UDEPT-based mechanochemical combination therapies for the treatment of cancer.
A Transferrin-Conjugated Hollow Nanoplatform for Redox-Controlled and Targeted Chemotherapy of Tumor with Reduced Inflammatory Reactions: Erratum
Authors: Jun Zhou, Menghuan Li, Wei Qi Lim, Zhong Luo, Soo Zeng Fiona Phua, Runlan Huo, Liqi Li, Ke Li, Liangliang Dai, Junjie Liu, Kaiyong Cai, Yanli Zhao
Journal: Theranostics (2022)

[This corrects the article DOI: 10.7150/thno.21194.].
A cell-penetrating whole molecule antibody targeting intracellular HBx suppresses hepatitis B virus via TRIM21-dependent pathway: Erratum
Authors: Jun-Fang Zhang, Hua-Long Xiong, Jia-Li Cao, Shao-Juan Wang, Xue-Ran Guo, Bi-Yun Lin, Ying Zhang, Jing-Hua Zhao, Ying-Bin Wang, Tian-Ying Zhang, Quan Yuan, Jun Zhang, Ning-Shao Xia
Journal: Theranostics (2022)

[This corrects the article DOI: 10.7150/thno.20047.].
Autophagy-lysosome inhibitor chloroquine prevents CTLA-4 degradation of T cells and attenuates acute rejection in murine skin and heart transplantation: Erratum
Authors: Jikai Cui, Jizhang Yu, Heng Xu, Yanqiang Zou, Hao Zhang, Shanshan Chen, Sheng Le, Jing Zhao, Lang Jiang, Jiahong Xia, Jie Wu
Journal: Theranostics (2022)

[This corrects the article DOI: 10.7150/thno.43507.].
Tumor microenvironment-activated single-atom platinum nanozyme with H<sub>2</sub>O<sub>2</sub> self-supplement and O<sub>2</sub>-evolving for tumor-specific cascade catalysis chemodynamic and chemoradiotherapy
Authors: Qiqi Xu, Yuetong Zhang, Zulu Yang, Guohui Jiang, Mingzhu Lv, Huan Wang, Chenghui Liu, Jiani Xie, Chengyan Wang, Kun Guo, Zhanjun Gu, Yuan Yong
Journal: Theranostics (2022)

Nanozyme-based tumor collaborative catalytic therapy has attracted a great deal of attention in recent years.However, their cooperative outcome remains a great challenge due to the unique characteristics of tumor microenvironment (TME), such as insufficient endogenous hydrogen peroxide (H2O2) level, hypoxia, and overexpressed intracellular glutathione (GSH).Methods: Herein, a TME-activated atomic-level engineered PtN4C single-atom nanozyme (PtN4C-SAzyme) is fabricated to induce the "butterfly effect" of reactive oxygen species (ROS) through facilitating intracellular H2O2 cycle accumulation and GSH deprivation as well as X-ray deposition for ROS-involving CDT and O2-dependent chemoradiotherapy.Results: In the paradigm, the SAzyme could boost substantial •OH generation by their admirable peroxidase-like activity as well as X-ray deposition capacity.Simultaneously, O2 self-sufficiency, GSH elimination and elevated Pt 2+ release can be achieved through the self-cyclic valence alteration of Pt (IV) and Pt (II) for alleviating tumor hypoxia, overwhelming the anti-oxidation defense effect and overcoming drug-resistance.More importantly, the PtN4C-SAzyme could also convert O2 •-into H2O2 by their superior superoxide dismutase-like activity and achieve the sustainable replenishment of endogenous H2O2, and H2O2 can further react with the PtN4C-SAzyme for realizing the cyclic accumulation of •OH and O2 at tumor site, thereby generating a "key" to unlock the multi enzymes-like properties of SAzymes for tumor-specific self-reinforcing CDT and chemoradiotherapy.Conclusions: This work not only provides a promising TME-activated SAzyme-based paradigm with H2O2 self-supplement and O2-evolving capacity for intensive CDT and chemoradiotherapy but also opens new horizons for the construction and tumor catalytic therapy of other SAzymes.
Genome instability is associated with ethnic differences between Asians and Europeans in hepatocellular carcinoma
Authors: Neslihan A. Kaya, Jianbin Chen, Hannah Lai, Hechuan Yang, Liang Ma, Xiaodong Liu, Jacob Santiago Alvarez, Jin Liu, Axel M. Hillmer, David Tai, Joe Yeong Poh Sheng, Zheng Hu, Yun Shen Chan, Pierce K.H Chow, Yuguang Mu, Torsten Wuestefeld, Weiwei Zhai
Journal: Theranostics (2022)

Hepatocellular carcinoma (HCC) is one of the deadliest cancer types with diverse etiological factors across the world.Although large scale genomic studies have been conducted in different countries, integrative analysis of HCC genomes and ethnic comparison across cohorts are lacking.Methods: We first integrated genomes of 1,349 HCC patients from five large cohorts across the world and applied multiple statistical methods in identifying driver genes.Subsequently, we systematically compared HCC genomes and transcriptomes between Asians and Europeans using the TCGA cohort.Results: We identified 29 novel candidate driver genes, many of which are infrequent tumor suppressors driving late-stage tumor progression.When we systematically compared ethnic differences in the genomic landscape between Asian and European HCCs using the TCGA cohort (n = 348), we found little differences in driver frequencies.Through multi-modal integrative analysis, we found higher genomic instability in Asians together with a collection of molecular events ranging from tumor mutation burden (TMB), copy number alterations as well as transcriptomic subtypes segregating distinctively between two ethnic backgrounds.Strikingly, we identified an Asian specific transcriptomic subtype with multiple ethnically enriched genomic alterations, in particular chromosome 16 deletion, leading to a clinically aggressive RNA subgroup unique to Asians.Integrating multi-modal information, we found that survival models predict patient prognosis much better in Asians than in Europeans, demonstrating a higher potential for precision medicine applications in Asia. Conclusion:For the first time, we have uncovered an unprecedented amount of genomic differences segregating distinctively across ethnicities in HCC and highlighted the importance of differential disease biology and management in HCC across ethnic backgrounds.
Plasma lipids signify the progression of precancerous gastric lesions to gastric cancer: a prospective targeted lipidomics study
Authors: Zong-Chao Liu, Wen-Hui Wu, Sha Huang, Zhong-Wu Li, Xue Li, Guang-Hou Shui, Sin Man Lam, Bo-Wen Li, Zhe-Xuan Li, Yang Zhang, Tong Zhou, Wei-Cheng You, Kai-Feng Pan, Wen-Qing Li
Journal: Theranostics (2022)

Rationale: Gastric cancer (GC) is preceded by a stepwise progression of precancerous gastric lesions. Distinguishing individuals with precancerous gastric lesions that have progression potential to GC is an important need. Perturbated lipid metabolism, particularly the dysregulation of de novo lipogenesis, is involved in gastric carcinogenesis. We conducted the first prospective lipidomics study exploring lipidomic signatures for the risk of gastric lesion progression and early GC. Methods: Our two-stage study of targeted lipidomics enrolled 400 subjects from the National Upper Gastrointestinal Cancer Early Detection Program in China, including 200 subjects of GC and different gastric lesions in the discovery and validation stages. Of validation stage, 152 cases with gastric lesions were prospectively followed for the progression of gastric lesions for a median follow-up of 580 days (interquartile range 390-806 days). We examined the lipidomic signatures associated with the risk of advanced gastric lesions and their progression to GC. Our published tissue proteomic data were referred to further investigate highlighted lipids with their biologically related protein expression in gastric mucosa. Results: We identified 11 plasma lipids significantly inversely associated with the risk of gastric lesion progression and GC occurrence. These lipids were integrated as latent profiles to identify 5 clusters of lipid expression that had distinct risk of gastric lesion progression. The latent profiles significantly improved the ability to predict the progression potential of gastric lesions (AUC: 0.82 vs 0.68, Delong's P = 4.6×10-4) and risk of early GC (AUC: 0.81 vs 0.55, P = 6.3×10-5). Significant associations were found between highlighted lipids, their biologically correlated proteins and the risk of GC, supporting the role of the pathways involving monocarboxylic acid metabolism and lipid transport and catabolic process in GC. Conclusions: Our study revealed the lipidomic signatures associated with the risk of gastric lesion progression and GC occurrence, exhibiting translational implications for GC prevention.
Challenges and opportunities to penetrate the blood-brain barrier for brain cancer therapy
Authors: Dannielle H. Upton, Caitlin Ung, Sandra M. George, Maria Tsoli, Maria Kavallaris, David S. Ziegler
Journal: Theranostics (2022)

Despite significant advances in research, the prognosis for both primary and secondary brain cancers remains poor.The blood-brain barrier (BBB) is a complex and unique semi-permeable membrane that serves as a protective structure to maintain homeostasis within the brain.However, it presents a significant challenge for the delivery of therapeutics into the brain and tumor.Some brain tumors are known to compromise BBB integrity, producing a highly heterogeneous vasculature known as the blood-tumor-barrier (BTB).Identifying strategies to bypass these obstacles to improve the penetrability of anticancer therapeutics has been the focus of research in this area.In this review, we discuss the strategies that have been investigated to evade or alter the cellular and molecular barriers of both the BBB and the BTB and detail the methods currently under preclinical or clinical investigation, including molecular, biological, and physical processes to overcome the BBB or BTB.Increased understanding of the BBB and BTB and the current methods of overcoming these barriers will enable the development of new and more effective treatment strategies for brain tumors.
Surface-engineered extracellular vesicles for targeted delivery of therapeutic RNAs and peptides for cancer therapy
Authors: Migara Kavishka Jayasinghe, Marco Pirisinu, Yuqi Yang, Boya Peng, Thach Tuan Pham, Chang Yu Lee, Melissa Tan, Luyen Tien Vu, Xuan TT Dang, Tin Chanh Pham, Huan Chen, Anskar Y.H. Leung, William C. Cho, Jiahai Shi, Minh TN Le
Journal: Theranostics (2022)

The advent of novel therapeutics in recent years has urged the need for a safe, non-immunogenic drug delivery vector capable of delivering therapeutic payloads specifically to diseased cells, thereby increasing therapeutic efficacy and reducing side effects. Extracellular vesicles (EVs) have garnered attention in recent years as a potentially ideal vector for drug delivery, taking into account their intrinsic ability to transfer bioactive cargo to recipient cells and their biocompatible nature. However, natural EVs are limited in their therapeutic potential and many challenges need to be overcome before engineered EVs satisfy the levels of efficiency, stability, safety and biocompatibility required for therapeutic use. Here, we demonstrate that an enzyme-mediated surface functionalization method in combination with streptavidin-mediated conjugation results in efficient surface functionalization of EVs. Surface functionalization using the above methods permits the stable and biocompatible conjugation of peptides, single domain antibodies and monoclonal antibodies at high copy number on the EV surface. Functionalized EVs demonstrated increased accumulation in target cells expressing common cancer associated markers such as CXCR4, EGFR and EpCAM both in vitro and in vivo. The functionality of this approach was further highlighted by the ability of targeting EVs to specifically deliver therapeutic antisense oligonucleotides to a metastatic breast tumor model, resulting in increased knockdown of a targeted oncogenic microRNA and improved metastasis suppression. The method was also used to equip EVs with a bifunctional peptide that targets EVs to leukemia cells and induces apoptosis, leading to leukemia suppression. Moreover, we conducted extensive testing to verify the biocompatibility, and safety of engineered EVs for therapeutic use, suggesting that surface modified EVs can be used for repeated dose treatment with no detectable adverse effects. This modular, biocompatible method of EV engineering offers a promising avenue for the targeted delivery of a range of therapeutics while addressing some of the safety concerns associated with EV-based drug delivery.
Orally administered titanium carbide nanosheets as anti-inflammatory therapy for colitis
Authors: Linqian Hou, Fei Gong, Bo Liu, Xiaoyuan Yang, Linfu Chen, Guangqiang Li, Yuehan Gong, Chao Liang, Nailin Yang, Xian Shen, Zhuang Liu, Liang Cheng
Journal: Theranostics (2022)

Rationale: Oxidative stress, resulting from excessive reactive oxygen species (ROS), plays an important role in the initiation and progression of inflammatory bowel disease (IBD).Therefore, developing novel strategies to target the disease location and treat inflammation is urgently needed.Methods: Herein, we designed and developed a novel and effective antioxidant orally-administered nanoplatform based on simulated gastric fluid (SGF)-stabilized titanium carbide MXene nanosheets (Ti3C2 NSs) with excellent biosafety and multiple ROS-scavenging abilities for IBD therapy.Results: This broad-spectrum and efficient ROS scavenging performance was mainly relied on the strong reducibility of Ti-C bound.Intracellular ROS levels confirmed that Ti3C2 NSs could efficiently eliminate excess ROS against oxidative stress-induced cell damage.Following oral administration, negatively-charged Ti3C2 NSs specifically adsorbed onto the positively-charged inflamed colon tissue via electrostatic interaction, leading to efficient therapy of dextran sulfate sodium salt (DSS)-induced colitis.The therapeutic mechanism mainly attributed to decreased ROS levels and pro-inflammatory cytokine secretion, and increased M2-phenotype macrophage infiltration and anti-inflammatory cytokine secretion, efficiently inhibiting inflammation and alleviating colitis symptoms.Due to their excellent ROS-scavenging performance, Ti3C2-based woundplast also promoted skin wound healing and functional vessel formation.Conclusions: Our study introduces redox-mediated antioxidant MXene nanoplatform as a novel type of orally administered nanoagents for treating IBD and other inflammatory diseases of the digestive tract.
Selenium nanoparticles alleviate ischemia reperfusion injury-induced acute kidney injury by modulating GPx-1/NLRP3/Caspase-1 pathway
Authors: Shaobo Wang, Yin Chen, Songling Han, Yong Liu, Jining Gao, Yinghui Huang, Wei Sun, Junping Wang, Cheng Wang, Jinghong Zhao
Journal: Theranostics (2022)

Rationale: Acute kidney injury (AKI) is a common critical illness in the clinic and currently lacks effective treatment options.Ischemia reperfusion injury (IRI) is a major pathogenic factor for AKI.Due to the deficiency of selenium (Se) in AKI patients, we intended to treat IRI-induced AKI using a Se rebalancing strategy in the present study.Methods: Sodium selenate, ascorbic acid, and bovine serum albumin (BSA) were employed to prepare nanomaterials termed Se@BSA nanoparticles (NPs) using a simple method.Experiments with human renal tubular epithelial HK-2 cells exposed to hypoxia/reoxygenation (H/R) and IRI-AKI mice were used to evaluate the therapeutic efficiency of Se@BSA NPs.Transcriptome sequencing, further molecular biology experiments, and pathologic analysis were performed to investigate the underlying mechanisms.Results: Se@BSA NPs accumulated in mouse kidneys and could be endocytosed by renal tubular epithelial cells after intravenous administration.In vitro studies showed that Se@BSA NP treatment markedly increased the levels of glutathione peroxidase (GPx)-1 and suppressed NLRP3 inflammasome activation in H/R cells, which resulted in reductions in the proteolytic cleavage of pro-Caspase-1 into active Caspase-1 and the maturation of inflammatory factors.Mouse experiments confirmed these findings and demonstrated an inspiring mitigative effect of Se@BSA NPs on IRI-induced AKI.Owing to modulation of the GPx-1/NLRP3/Caspase-1 pathway, Se@BSA NPs dramatically inhibited fibrosis formation after AKI. Conclusion:This study provides an effective therapeutic option by applying easy-to-produce Se-containing nanomaterials to remedy Se imbalance and impede inflammatory responses in the kidney, which is a promising candidate for AKI treatment.
Crosstalk between macrophage-derived PGE<sub>2</sub> and tumor UHRF1 drives hepatocellular carcinoma progression
Authors: Jian Zhang, Hongyan Zhang, Xiuli Ding, Jia Hu, Yongkui Li, Jinxiang Zhang, Hui Wang, Shanshan Qi, Aqing Xie, Jie Shi, Mengxi Xiang, Yawen Bin, Guobin Wang, Lin Wang, Zheng Wang
Journal: Theranostics (2022)

Background: Tumor-associated macrophages (TAMs) and dysregulated tumor epigenetics contribute to hepatocellular carcinoma (HCC) progression. However, the mechanistic interactions between TAMs and tumor epigenetics remain poorly understood. Methods: Immunohistochemistry and multiplexed fluorescence staining were performed to evaluate the correlation between TAMs numbers and UHRF1 expression in human HCC tissues. PGE2 neutralizing antibody and COX-2 inhibitor were used to analyze the regulation of TAMs isolated from HCC tissues on UHRF1 expression. Multiple microRNA prediction programs were employed to identify microRNAs that target UHRF1 3'UTR. Luciferase reporter assay was applied to evaluate the regulation of miR-520d on UHRF1 expression. Chromatin immunoprecipitation (ChIP) assays were performed to assess the abundance of H3K9me2 in the KLF6 promoter and DNMT1 in the CSF1 promoter regulated by UHRF1. The functional roles of TAM-mediated oncogenic network in HCC progression were verified by in vitro colony formation assays, in vivo xenograft experiments and analysis of clinical samples. Results: Here, we find that TAMs induce and maintain high levels of HCC UHRF1, an oncogenic epigenetic regulator. Mechanistically, TAM-derived PGE2 stimulates UHRF1 expression by repressing miR-520d that targets the 3'-UTR of UHRF1 mRNA. In consequence, upregulated UHRF1 methylates H3K9 to diminish tumor KLF6 expression, a tumor inhibitory transcriptional factor that directly transcribes miR-520d. PGE2 reduces KLF6 occupancy in the promoter of miR-520d, dampens miR-520d expression, and sustains robust UHRF1 expression. Moreover, UHRF1 promotes CSF1 expression by inducing DNA hypomethylation of the CSF1 promoter and supports TAM accumulation. Conclusions: Capitalizing on studies on HCC cells and tissues, animal models, and clinical information, we reveal a previously unappreciated TAM-mediated oncogenic network via multiple reciprocal enforcing molecular nodes. Targeting this network may be an approach to treat HCC patients.